Immune-mediated rejection is the principal obstacle to the use of heart transplantation for the treatment of end-stage cardiac failure. Current immunosuppressive regimens have limited efficacy and are associated with substantial toxicity. The key final common pathways of transplant rejection include the production of the toxic oxidant peroxynitrite, the free radical nitric oxide, and the prostaglandin thromboxane. Inotek, Inc. has developed a revolutionary immunosuppressive agent, mercaptoethylguanidine (MEG), which interferes with all 3 pathways simultaneously, acting as a potent scavenger of peroxynitrite, an inhibitor of cyclooxygenase, and a selective inhibitor of the inducible nitric oxide synthase. The Specific Aim of this Phase I SBIR proposal is to establish whether MEG prevents organ dysfunction and cellular injury in an experimental model of transplant rejection. This hypothesis will be tested using a well- established rat heterotopic cardiac transplantation system. Demonstration that MEG prevents tissue injury and prolongs graft survival in this model would represent a breakthrough in the design of novel immunosuppressive regimes for transplant rejection and would justify continued commercial development of MEG. Phase II SBIR funding would be used to support pre- clinical toxicology/pathology and Phase I clinical studies.